The present invention relates to encapsulated products. More particularly, the present invention relates to a hybrid membrane bead and process for the encapsulation of bioactive materials in semi-permeable hybrid membrane beads of gel forming polymers.
Encapsulation processes are finding increasing use in a variety of areas of biotechnology. Such processes are used to encapsulate various materials such as enzymes, hormones, drugs, adsorbents and cells which can then be used in bioreactors, artificial organs, bioseparation systems, controlled drug-release systems, and so forth. Prior art processes often require harsh conditions such as the use of non-aqueous solvents, extremes of pH, or high temperature. Such techniques are inherently unsuitable for encapsulating delicate biological materials such as live cells and labile proteins.
Ideally, encapsulation techniques for biological materials should use mild conditions and a membrane material which is inert and non-toxic to the material being encapsulated. The encapsulation technique should also provide a semi-permeable membrane and allow for adjustment of membrane thickness and membrane pore size. Preferably, the charge on the membrane should be adjustable to suit different applications. The membrane should also be strong enough to withstand liquid-shear or the friction effects arising out of agitation.
A well known membrane encapsulation method is the poly (L-lysine) --alginate membrane method which involves formation of a polyelectrolyte membrane complex. In this method the mixture of bioactive material and sodium alginate is extruded through a droplet forming device into a buffer containing calcium chloride. The Ca.sup.+2 cations cross-link the alginate matrix almost instantaneously to form gel beads. The beads are then treated with poly-1-lysine to displace the calcium ions in the outer layer to form a polyelectrolyte-complex membrane. Calcium alginate gel in the interior of the bead is then liquefied using a calcium chelating agent.
However the poly (L-lysine) alginate method of membrane encapsulation involves a large number of processing steps and results in a membrane which is charged due to its polyelectrolyte nature. Also, the membrane formed has relatively poor mechanical strength and poor chemical stability in the presence of electrolytes such as heparin, polysulfonic acid and polyphosphoric acids which interact more strongly with alginate or poly (L-lysine). Furthermore, liquefied alginate remaining within the membrane bead may pose certain problems. For example, alginate can interfere with the functioning of biomaterial by complexing with multivalent ions or other charged macromolecules. Alginate can also adsorb on positively charged surfaces and cause fouling. In addition, this and other methods of encapsulation are capable of immobilizing only one population of biological material evenly distributed through the gel matrix or bead.
Thus, there remains a need for an improved process for encapsulation of bioactive materials and it is an object of the present invention to provide such an improved process. It is another object of the invention to provide a membrane bead and process of encapsulation which can immobilize more than one biological population and/or populations at different concentrations or with different distributions within the membrane bead. Further understanding of this invention will be had from the following description and claim. All parts and percentages herein are by weight unless otherwise indicated.